1. How to Survive an FDA Inspection
Patricia S. Kerby, MPA
Office of Human Subjects Protection
January 7, 2009

2. Why are Inspections Done?
Protect the rights and welfare of human subjects
Assure quality and integrity of data
Ensure compliance with regulatory requirements

3. When are Inspections Done?
Clinical Investigator inspections are performed:
For most clinical trials that support primary claims of efficacy and safety.
For trials supporting important efficacy supplements
Studies of any phase if there is data integrity concerns
Phase IV studies

4. Who is inspected?
Investigator sites are selected for inspection based on multiple factors:
Importance of study
Statistical importance of the data
History of the Clinical Investigator
Importance- to labeling and size of number of outliers
History, including previous inspections and findings

5. How to Prepare for a Successful Inspection
Accommodate the Inspector. Requests for an inspection are usually less than 2 weeks.
You should speak directly with the FDA Inspector whenever possible to arrange the inspection date.
Inspectors must report “undue delay” in scheduling which is usually more than 10 days without sufficient justification.
This is your first opportunity to develop a positive relationship with the Inspector.

6. Prepare for a Successful Inspection
Ask the inspector about the nature and scope of the visit.
How many inspectors are coming and how long they planning to be on site.
Could they provide you with a list of subjects they would like to review.
Identify the time they will arrive and set that time for the introductory meeting.
Notify your sponsor of the inspection.
Ask in a manner that suggests you are only trying to prepare so their visit will go smoothly
This helps you to provide the medical records in a timely manner
They will probably provide assistance in preparation

7. Prepare for a Successful Inspection
Approach the Inspection as an opportunity to learn.
Identify Roles during the Inspection
List staff names and positions
Assign one person responsible for making copies for the inspector.
Arrange for adequate work space for the inspector
Away for busy areas
Empty of any records
Comfortable
Including contact information. Invite them to the planning meeting
Maintain a log of all copied materials. Make one copy for the inspector, one for the site and the sponsor may request a copy.

8. Prepare for a Successful Inspection
Anticipate needing:
List of all studies performed by the investigator
List of all 1572s
List of all labs used, certificates, and normals
Copies of all protocols, IRB approvals, approval of changes, consents
List of all staff, signature list, delegation list
IRB name, address, chairperson
Monitoring log, telephone contact records
Information and contacts for electronic record system
Most of this information is located in the Regulatory Binder/files. All items should be easy to locate and filed chronologically.

9. Prepare for a Successful Inspection
All Study staff should be prepared to be interviewed
Principle Investigator should anticipate being asked to:
Describe orientation/training on test article, protocol, Investigator obligations
Describe delegation of authority and how you retain control and knowledge of the study
Describe on-going communications with sponosor
Who does subject consenting and how
Who dispenses test article

10. During the Inspection
The Inspector should present their official credentials and a form 482 Notice of Inspection
Meet with the Inspector and set an agenda for the visit. Allow time at the end of each day to meet with Inspector to answer questions, or provide clarification. This can help avoid additional exploration or misunderstanding by the Inspector. If the Inspector identifies a problem/issue that you have addressed through process improvement let the Inspector know.

11. During the Inspection
A staff member should be available to the Inspector to request additional record or copies at all times. Show the Inspector where comfort facilities are located. It is OK to offer snacks to the Inspector that are available for all staff.
The Inspector is required to notify the District Office of any refusal to provide or copy requested records. They do not generally ask for contractual or Quality Assurance records. Review you institutional policies on this matter before the inspection.

12. What Will the Inspector Look For?
General condition of source documentation
ALCOA- Attributable, Legible, Contemporaneous, Original, Accurate
Adequate documentation that all subjects existed
Compare Source, CRFs and data listings (AE/SAEs)
Subjects meet inclusion criteria
Subject baseline condition and condition throughout trial
Identity of all persons obtaining data

13. What Will the Inspector Look For?
Number of subjects screened, entered, dropped. Date of first and last entry
Review of consent obtained for all subjects ( correct, approved versions)
IRB records, reports, and actions maintained. IRB approval received prior to enrolling subjects.
All deaths, SAEs and safety reports reported to the IRB
Did the Investigator provide or report to sponsor all required items.

14. What Will the Inspector Look For?
Did the sponsor adequately monitor the trial
Test article accountability procedures: receipt, dispensing, Lot #/ID, correct dose calculations, correct administration, appropriate disposition
Adverse findings in any area are likely to increase overall intensity of inspection. Well organized, easy to review records send a strong, positive message.

15. General Inspection Instructions for All Staff
Always answer truthfully
Do not answer a question until you have heard and understood the whole question. If you do not fully understand what the Inspector wants, ask “Would you please restate the question”
Answer only the question asked
Answer questions with yes or no whenever possible
Do not answer questions outside your area of responsibility
Do not volunteer additional information

16. General Inspection Instructions for All Staff
If you do not know the answer to a question, state that you do not know the answer, do not speculate.
Speak clearly, slowly and at a reasonable volume
Beware of pauses
Beware of being asked the same question twice.
Do not bring documents in to the inspection area that have not been requested
Dress professionally
Do not feel that you need to keep talking
This is done to see if you will answer the same way- don’t assume that it is because you did not answer correctly or fully

17. What Will the Inspector Find?
Common Clinical Investigator Deficiencies*
54% failure to follow investigational plan
16% protocol deviations
24% issues with Informed Consent documentation
14% inadequate device/drug accountability
13% lack of FDA &/or IRB approval
*2004 numbers

18. What Will the Inspector Find?
Common Sponsor Deficiencies*
40% inadequate monitoring
21% failure to secure investigator compliance
16% inadequate device accountability
11% failure to obtain FDA/IRB approval
*2004 numbers
The OIG report Sponsors not reporting conflict of interest for their Pis. A 2003 article in JAMA estimated 23 to 28 percent of academic researchers have financial interests in medical companies. The OIG found that the FDA reported 1% of their investigators disclosed financial interest.

19. The Final Hour
At the inspection close out meeting the Inspector will review their general findings with you. If there are no regulatory deficiencies, that will be the end of the inspection. You should receive a letter from the FDA documenting the inspection some time later.
If the Inspector has identified regulatory deficiencies you will receive a 483 Inspectional Observations form outlining the deficiencies.

20. The Final Hour
If you are presented a 483, review the items with the Inspector. If the deficiency identified has already had a corrective action put in place tell the Inspector. If there was a misunderstanding, provide the information necessary to clarify. Accept the findings with grace and let the Inspector know you will carefully review the findings and forward your response. Thank the Inspector for their time and commitment.

21. 483 Response
You are not required to respond to a 483. The FDA will review all of the information gathered by the Inspector and reserves the opportunity to expand or contract the items listed. You will receive a letter from the FDA outlining the findings and a request to respond.
It is recommended to respond to the 483 prior to receiving a letter. This is especially important if there are items that you can successfully clarify with documentation, or if the 483 is ‘significant’.

22. Responding to the 483 The response should be from the Investigator.
Explain and provide documentation if there were any mistakes or misunderstandings by the Inspector.
For everything else Accept Responsibility
Evaluate the errors and identify what happened to cause the deficiency
Tell the FDA what you have done/will do to ensure it will not happen again
Request that your redacted response be included with any release of you 483 through the FOIA.
#2 They are human and they do make mistakes. Check the 483 carefully.
#3 I have looked at a number of response letters from the PIs to the FDA, they want detailed information on what corrective action steps were taken and what steps have been implemented to keep it from happening in the future. You could also note the you are committed to improving and learned from the experience.
#4 Freedom of Information Act.

23. Responding to the 483
If your response is completed in a timely manner it will be included in the review of the inspectional materials. Usually you will receive a letter outlining the 483 items and noting your response.
If your response is not acceptable or the findings are serious additional actions may take place.
Request for additional corrective/improvement plans
You may have additional inspections
You may receive a warning letter with additional actions required
Most serious cases receive NIDPOE or NOOH letters
Notification Of Initiation of Disqualification Proceedings and Opportunity to Explain
Notification of Opportunity for Hearing.